Relationships Between Risk for Type 2 Diabetes, Restorative Yoga, and Circulating MicroRNAs Project summary Type 2 diabetes is priority for both public health and precision medicine. The etiology of type 2 diabetes is complex and both genetic and behavioral/environmental factors contribute to risk. Current approaches to risk prediction and risk reduction are limited because they fail to account for the interactions between risk factors. MicroRNAs regulate expression of genes in response to behavioral and environmental exposures. Circulating microRNAs, which are readily detectable in blood, are emerging as useful indicators of disease etiology and show changes in response to the environment and behaviors. We previously showed that circulating microRNAs are associated with risk for type 2 diabetes and response to an insulin sensitizing pharmacologic agent. Our own prior studies and others have been cross-sectional and therefore provided limited information about the insights that microRNAs may provide about the mechanisms underlying development of type 2 diabetes. The first aim of this study is to evaluate the trajectories of circulating microRNAs and fasting blood glucose over time. We will measure microRNAs in banked plasma samples from participants in the the recently completed 48-week NIH-funded randomized Practicing Restorative Yoga vs. Stretching for the Metabolic Syndrome (PRYSMS) trial that tested the effect of restorative yoga on fasting blood glucose in individuals at risk for type 2 diabetes (n=171). Participants in the restorative yoga group (n=88) had a significant decrease in fasting blood glucose after 12 months compared to an active stretching control group. The existing phenotypic data and biologic specimens collected at five time points in the PRYSMS trial provide an exceptional opportunity to evaluate the relationships between longitudinal changes in both microRNAs and fasting blood glucose in an extremely well characterized sample of individuals who underwent an intervention that decreased their fasting blood glucose. The second aim of this study is to determine whether microRNAs predict changes in fasting blood glucose after 12-months. Circulating microRNAs will be measured using a flow cytometry-based direct detection assay followed by validation of significant targets by quantitative polymerase chain reaction. This study will be the first to evaluate the relationships between circulating microRNAs and fasting blood glucose over time. This knowledge will improve our understanding of inter-individual variability in mechanisms underlying type 2 diabetes. These insights can be used to improve risk detection, risk stratification, and optimization of risk reduction interventions based on individual biology.